Histone acetylase and deacetylase inhibitors

Readers, please don’t turn off on this post because the subject sounds too technical.It relates to a major application area of epigenomics that has a lot to do with aging and anti-aging science.

First, a simplified review of a few key concepts.Histones are spindles in a cell’s nucleus around which DNA is wrapped; they play important roles in gene activation.Histone acetylation is a chemical modification of a portion of a histone which leads to selective unwrapping of the DNA making the exposed genes amenable to activation and expression.Histone deacetylation is the opposite.It is done by histone deacetylases and wraps up the DNA making the associated genes unreachable by activating proteins and therefore less amenable to expression.Gene transcription is repressed.Histone deacetylase inhibitorsprevent the actions of histone deacetylases, that is, they keep the DNA unwrapped and available for gene expression.The enzymes controlling the state of histone acetylation in vivo are histone acetyltransferase (HAT) and histone deacetylases (HDAC). HDAC enzymes catalyze the removal of acetyl groups from the amino-terminal lysine residues of core nucleosomal histones.The result is gene silencing.Exactly how the HAT and HDAC enzymes work is complex and only partially understood(ref).There is a whole mammalian HDAC gene family and a corresponding HAT gene family. Patterns of histone acetylation are part of the epigenomic history of a cell.For background see my previous posts Epigenetics, epigenomics and agingand DNA methylation, personalized medicine and longevity.

One reason for the current interest in HAT and HDAC is that histone deacetylase inhibitors appear to act as powerful inducers of differentiation or apoptosis in cancer cells.See this earlier review article and check out some of the articles citing it, particularly the more recent ones. It appears that inhibiting HDAC may become an important weapon in anti-cancer therapies(ref,ref).HDAC inhibition may be effective against some skin cancers and leukemias.HDAC inhibitors are reported to show promise against head and neck cancer.The applications of HDAC and HAT inhibition extend to other medical conditions beyond cancers.HDAC inhibitors may be useful for damping down the immune response in patients receiving bone marrow transplants(ref)(ref).On another front. recent research suggesting that microRNAs and over-activity of histone deacetylases may be root causes of the auto-immune disease systemic lupus erythematosus (SLE).The cited article reports there is “further rationale for the use of histone deacetylase inhibitors (HDIs) for the treatment of lupus.”Further the researcher Nilamadhab Mishra is reported to be investigating “– two HDIs — TSA (Trichostatin A) and SAHA (suberoylaniide hydroxamic acid ) — in lupus patients and has reported positive results against a number of lupus symptoms and conditions.”

Histone acetylation and deacetylation are implicated in a number of the theories of aging treated in my ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY treatise, We find a number ofHAT and HDAC inhibitors in the anti-aging firewall dietary regimen. (E )-Resveratrol appears to inhibit histone deacetylase activity in a concentration-dependent manner according to a recent research publication.The publication suggests that for this reason, resveratrol “could be a promising candidate for the treatment of spinal muscular atrophy.”Resveratrol’s actions are complex, however.It activates protein deacetylase SIRT1, and this is thought to be the main reason why it has anti-aging activity(ref).

In discussing the Programmed epigenomic changes theory of aging my in treatise, I have written about how inhibition of NF-kappaB expression is being considered as a treatment for cancers and other diseases and how this also qualifies as an anti-aging strategy. It appears that deacetylation and acetylation events are implicated in the regulation of NF-kappaB transcriptional activity at multiple levels(ref). There is is a longevity-related connection between histone H3 lysine 9 deacetylation and NF-kappaB gene expression, with SIRT6 playing an important linking role(ref). “SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters.”The result is that even if NF-kappaB gets into a cell’s nucleus, the wrapped-up histones keep it from activating genes that lead to inflammation and other age-related damage. The HDAC inhibitor trichostatin A and vitamin D3 are synergistic in their anti cancer-proliferation capabilities.Both work via the vitamin D3 receptor(ref)(ref).Some of curcumin’s anti-cancer powers may be due to its capability to inhibit HDAC activity(ref).In human hepatoma cells, curcumin treatment significantly inhibited the HAT activity both in vivo and in vitro(ref).There are multiple other links to the aging theories and related to the suggested supplements as well.Many of the relationships are complex.Curcumin, for example, works against cancer in multiple ways: to inhibit HDAC, to prevent degredation of IK-alpha (the substance that keeps NF-kappaB bound in the cell cytoplasm), to inhibit translocation of the NF-kappaB/p65 subunit into the nucleus, and to inhibit expression of th Notch1 gene(ref).

The bottom line is that we can expect to hear more and more about HAT and HDAC inhibition in the course of future anti-aging science reporting and might as well get used to that.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com.
Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.

Prophets: Interesting combination. I am sure there are other HDAC inhibitors in the combined firewall, but it looks like a most of the substances have not yet been researched from this viewpoint. I did see one study indicating that wild ginger is a powerful HDAC inhibitor.

I am gettting deeper into the new body of research on the epigenomics of Lupus, however, a subject of great interest because my wife Melody has recently had a very threatening Lupus flare. This article http://www.jimmunol.org/cgi/content/full/176/12/7143 and later publications that cite it are of particular interest. It appears that HDAC inhibitors may help. She is already taking curcumin and resveratrol. Perhaps she should start with sulforaphane too.